Heterocyclic carboxamides and their use as fungicides

ABSTRACT

Compounds of general formula (I), in which Het represents a five or six membered saturated, partially unsaturated or aromatic ring containing between one and six heteroatoms of the group N, O, S, in which the heterocycle is substituted in an adjacent manner with -P-Q i -T-Q 2 , -GZ and Y, such that the substituant -GZ is adjacent to both, the other substituants being as defined in the description, process for preparing this compound, fungicidal composition comprising this compound, method for treating plants by applying this compound or composition.

[0001] The present invention relates to new substituted heterocycles,their process of preparation, their use as fungicides, particularly inthe form of fungicidal compositions, and methods for the control ofphytopathogenic fungi of plants using these compounds or theircompositions.

[0002] Substituted heterocycles with fungicidal action are known in theliterature. Thus, substituted heterocycles, disclosed in particular inpatent application WO-A2-01/05769 and by M. Shimano et al. (TetrahedronLett. 1998, 12745-12774), are presented as being effective againstphytopathogenic fungi of plants. These compounds, and also thosedisclosed in patent WO-A2-01/143339, only present heterocycles that aresubstituted in an adjacent manner by a) amide, b) hydroxy (or aprocessor thereof and c) eventually an alkoxy (or thioalkoxy) radical.

[0003] Patent application WO-A-00/26191 presents picolinamidederivatives that are optionally substituted in position 4 with a methoxyradical. Patent application WO-A-95/25723 proposes 3-pyridylcarboxylicacid derivatives.

[0004] Picolinamide derivatives are also known from patent applicationJP-11 228 542. These derivatives are presented as having potentialantifungal activities and low toxicity, for use in pharmaceuticalproducts.

[0005] Other picolinic acid derivatives are also known from patentapplication EP-A-0 690 061, in which such compounds are used assynthetic intermediates for the preparation of pyridothiadiazoles.

[0006] However, some of these known compounds have the drawback of beingtoxic products, which forbids any use of these compounds in agriculturefor eradicating phytopathogenic diseases of crops. Others of thesecompounds are obtained from fermentation musts and have relativelycomplex chemical structures. Thus, the preparation and purification ofthese compounds remain demanding and expensive operations, making anyindustrial synthesis or marketing economically non-viable.

[0007] We have now found a new family of heterocyclic carboxamidederivative which do not possess the above mentioned drawbacks and whichhave an improved fungicidal activity.

[0008] Accordingly, the present invention provides heterocycliccarboxamide derivative of general formula (I):

[0009] in which:

[0010] Het represents a five or six membered saturated or partiallyunsaturated or aromatic ring containing one or two heteroatoms of thegroup N, O, and S which can be identical or different, in which theheterocycle is substituted by —(C═O)-Q¹-T-Q², -Gz and Y in an adjacentmanner, such that the substituent -Gz is adjacent to both Y and—(C═O)-Q¹-T-Q² and that —(C═O)-Q¹-T-Q², -Gz and Y are not linked withheteroatoms of Het;

[0011] n represents 0, 1, 2 or 3;

[0012] X is chosen in the group consisting of hydrogen, halogen, —R¹ and—SR¹;

[0013] Y is chosen in the group consisting of

[0014] —(C═O)—R³, —NH₂, —NHR¹, —NH—(C═O)—R² , —(SO₂)—R¹ and O;

[0015] G is chosen in the group consisting of —(CH₂)_(k)—, —O—,—O—(C═O)— and —O—(C═O)—O—;

[0016] z is chosen in the group consisting of hydrogen, —R¹ and halogen;

[0017] Q¹ is chosen in the group consisting of

[0018] T is chosen in the group consisting of —O—, —(CH₂)_(q)— and —S—;

[0019] Q² is chosen in the group consisting of hydrogen, —R¹, —R⁴,methylbenzothiazolyl,

[0020] j, k, m, p, q, r and t are independently chosen as being 0, 1, 2or 3;

[0021] h represents an integer between 0 and 10;

[0022] R¹ is C₁-C₄ alkyl or C₁-C₄ alkoxyalkyl;

[0023] R² is oxy-(C₁-C₄)alkylene or oxy-(C₁-C₄)alkyl;

[0024] R³ is —OH, —NH₂, oxy-(C₁-C₄)alkyl or oxy-(C₁-C₄)alkoxyalkyl;

[0025] and R⁴ is halogen, alkyl or halogenoalkyl;

[0026] as well as N-oxides, geometrical and/or optical isomers,enantiomers and/or diastereoisomers, tautomeric forms, salts and metaland metalloid complexes thereof, with proviso that —(C═O)-Q¹-T-Q² is notin the 2-position when Het represents a pyridine.

[0027] The tautomeric forms of the compound of general formula (I) arealso included in the present invention. By tautomeric forms it is to beunderstood all of the isomeric forms well known in the art and asdescribed in the work “The Tautomerism of Heterocycles, Advances inHeterocyclic Chemistry, Supplement 1, by J Elguero, C. Martin, A. R.Katritsky and P Linda, published by Academic Press, New York, 1976,pages 1-4.

[0028] The compound of general formula (I) can exist in one or moreforms of geometrical isomers according to the number of double bonds inthe compound. For example, compounds of general formula (I) can comprise2 different geometrical isomers denoted (E) or (Z) depending on theconfiguration of the two double bonds. The E and Z notation can bereplaced, respectively, by the term “syn” and “anti”, or “cis” and“trans”. Reference is made particularly to the work of E. Eliel and S.Wilen “Stereochemistry of Organic Compounds”, published by Wiley (1994),for the description and use of these notations.

[0029] “Het” of the compound of general formula (I) may be a fivemembered ring heterocycle. Preferably, “Het” is chosen in the groupconsisting of thiophene, pyrrole, isoxazole, isothiazole, pyrazole andpyrrolidine.

[0030] Specific examples of compounds of the present invention where Hetis a five membered heterocycle include

[0031] Het is thiophene,

[0032] n represents 0 or 1;

[0033] X is —H;

[0034] Y is chosen in the group consisting of —NH₂, —CO₂H, —NHC(O)R² and—S(O)₂—R¹;

[0035] R¹ is C₁-C₄ alkyl;

[0036] R² is oxy-(C₁-C₄)alkylene;

[0037] G is —O—;

[0038] Z is —H or —R¹;

[0039] Q¹ is

[0040] T is —O— or —(CH₂)_(q)—;

[0041] Q² is chosen in the group consisting of:

[0042] p and t are independently chosen as being 0, 1 or 2;

[0043] q is 0;

[0044] as well as the optional N-oxides, geometrical and/or opticalisomers, enantiomers and/or diastereoisomers, tautomeric forms, saltsand metal and metalloid complexes thereof.

[0045] A further example is where

[0046] Het is pyrrole;

[0047] n represent 0, 1 or 2;

[0048] X is —H or —R¹;

[0049] Y is chosen in the group consisting of —NH₂, —C(O)R³, —NHC(O)R²and —S(O)₂—R¹;

[0050] R¹ is C₁-C₄ alkyl;

[0051] R² is oxy-(C₁-C₄)alkylene;

[0052] R³ is —OH, oxy-(C₁-C₄)alkyl or oxy-(C₁-C₄)alkoxyalkyl;

[0053] G is —O—;

[0054] Z is —H or —R¹;

[0055] p and t are independently chosen as being 0, 1 or 2;

[0056] Q¹ is

[0057] T is —O— or —(CH₂)_(q)—;

[0058] q is 0;

[0059] Q² is chosen in the group consisting of hydrogen, —R¹, —R⁴,

[0060] as well as the optional N-oxides, geometrical and/or opticalisomers, enantiomers and/or diastereoisomers, tautomeric forms, saltsand metal and metalloid complexes thereof.

[0061] A further example is where:

[0062] Het is isoxazole;

[0063] n is 0;

[0064] Y is chosen in the group consisting of —NH₂, —C(O)R³, —NHC(O)R²and —S(O)₂—R¹;

[0065] R¹ is C₁-C₄ alkyl;

[0066] R² is oxy-(C₁-C₄)alkylene or oxy-(C₁-C₄)alkyl;

[0067] R³ is —OH, oxy-(C₁-C₄)alkyl or oxy-(C₁-C₄)alkoxyalkyl;

[0068] G is —O—;

[0069] Z is —H;

[0070] p and t are independently chosen as being 0, 1 or 2;

[0071] Q¹ is

[0072] T is —O— or —(CH₂)_(q)—;

[0073] q is 0;

[0074] Q² is chosen in the group consisting of

[0075] as well as the optional N-oxides, geometrical and/or opticalisomers, enantiomers and/or diastereoisomers, tautomeric forms, saltsand metal and metalloid complexes thereof.

[0076] A further example is where:

[0077] Het is pyrrolidin;

[0078] n is 1 or 2;

[0079] Y is O;

[0080] G is —O—;

[0081] Z is —H;

[0082] p and t are independently chosen as being 0, 1 or 2;

[0083] Q¹ is

[0084] T is —O— or —(CH₂)_(q)—;

[0085] q is 0;

[0086] Q² is chosen in the group consisting of hydrogen, —R¹, —R⁴,

[0087] as well as the optional N-oxides, geometrical and/or opticalisomers, enantiomers and/or diastereoisomers, tautomeric forms, saltsand metal and metalloid complexes thereof

[0088] “Het” of the compound of general formula (I) may be a sixmembered ring heterocycle. Preferably, Het is chosen in the groupconsisting of pyridine, such that —(C═O)-Q¹-T-Q² is attached in3-position, 1,2-pyridazine, such that —(C═O)-Q¹-T-Q² is attached in3-position and pyranone, such that —(C═O)-Q¹-T-Q² is attached in2-position.

[0089] Specific examples of compounds of the present invention where Hetis a six membered heterocycle include:

[0090] Het is pyridine, such that —(C═O)-Q¹-T-Q² is attached in3-position;

[0091] n represent 0, 1 or 2;

[0092] X is —H or —R¹;

[0093] Y is chosen in the group consisting of

[0094] , —(C═O)—R³, —NH₂, —NHR¹, —NH—(C═O)—R² , —(SO₂)—R¹ and —O;

[0095] R¹ is C₁-C₄ alkyl;

[0096] R² is oxy-(C₁-C₄)alkylene or oxy-(C₁-C₄)alkyl;

[0097] R³ is —OH, oxy-(C₁-C₄)alkyl or oxy-(C₁-C₄)alkoxyalkyl;

[0098] G is —O—;

[0099] Z is —H or —R¹;

[0100] p and t are independently chosen as being 0, 1 or 2;

[0101] Q¹ is

[0102] T is —O— or —(CH₂)_(q)—;

[0103] q is 0,;

[0104] Q² is chosen in the group consisting of:

[0105] as well as the optional N-oxides, geometrical and/or opticalisomers, enantiomers and/or diastereoisomers, tautomeric forms, saltsand metal and metalloid complexes thereof.

[0106] A further example is where:

[0107] Het is pyranone, such that —(C═O)-Q¹-T-Q² is attached in2-position;

[0108] n is 0, 1 or 2;

[0109] X is —H or —R¹

[0110] Y is O;

[0111] R¹ is C₁-C₄ alkyl;

[0112] G is —O—;

[0113] Z is —H;

[0114] p, q and t are independently chosen as being 0, 1 or 2;

[0115] Q¹ is

[0116] T is —O— or —(CH₂)_(q)—;

[0117] Q² is chosen in the group consisting of

[0118] as well as the optional N-oxides, geometrical and/or opticalisomers, enantiomers and/or diastereoisomers, tautomeric forms, saltsand metal and metalloid complexes thereof.

[0119] The compound of general formula (I) can exist in one or moreoptical isomeric or chiral forms according to the number of asymmetriccentres in the compound. The present invention thus also includes allthe optical isomers and their racemic or scalemic (scalemic designates amixture of enantiomers in different proportions), as well as themixtures of all possible stereoisomers in all proportions, including theracemic mixture. The separation of the diastereoisomers and/or opticalisomers can be effected by known methods (E. Eliel ibid.).

[0120] The present invention also relates to the process of preparationof the compound of general formula (I). Thus, according to a furtheraspect of the present invention there is provided a process for thepreparation of compound of general formula (I) as defined above, whichprocess is defined by scheme I:

[0121] by effecting a reaction between a substituted heterocyclic acidor acid derivative of general formula (a) with a nucleophilic compoundof general formula (b), wherein:

[0122] Y′ chosen in the group consisting of

[0123] , halogen, —NH₂, —NO₂, —(C═O)—R³, —NHR¹, —NH—(C═O)—R² , —(SO₂)—R¹and O;

[0124] G′ is chosen in the group consisting of —(CH₂)_(k)—, —O—,—O—(C═O)— and —O—(C═O)—O—;

[0125] z′ is chosen in the group consisting of hydrogen, —R¹, halogenand benzyl;

[0126] Y′, G′ and z′ may also form a substituted oxazolic ringdegradable to Y═NH₂ and G-z=OH;

[0127] X, Y, G, z, Q¹, T, Q² are as defined above;

[0128] W represents a hydroxy group (—OH) present in the free acid—(C═O)—OH or a group obtained after activation of the free acid—(C═O)—OH.

[0129] With regard to W of the compound of general formula (a), suitableexamples of the group obtained after activation of the free acid—(C═O)—OH include halo radical, alkylcarbonyloxy or alkylsulphonyloxy.

[0130] Compound of the general formula (I′) may optionally be convertedto compound of general formula (I) via some well known functional grouptransformations, such as:

[0131] reduction of a nitro group to an amino group with hydrogen in apresence of a catalyseur such as platinum or palladium on charcoal in aprotic solvent such as methanol under pressure;

[0132] deprotection of a protected amino or hydroxyl group to the freeamino or hydroxyl using acidic (such as boron tribromide indichloromethane or aqueous hydrochloric acid) or basic (sodium orpotassium hydroxyde aqueous solution) conditions;

[0133] substitution of a leaving group such as halide by a suitablenucleophile in the presence of a base in an aprotic solvent;

[0134] Curtius or Hofmann rearrangement as described by Banthorpe in Thechemistry of the azido group (1971) pp 397, or by Wallis in OrganicReactions (1946) pp 267.

[0135] The compound according to the present invention can be preparedaccording to the general method of preparation described above. It willnevertheless be understood that the skilled worker will be able to adaptthis method according to the specifics of each of the compounds, whichit is desired to synthesise.

[0136] The preparation of reagents used in one or other of the generalmethods of preparation is generally known and is generally describedspecifically in the prior art or in such a manner that the man skilledin the art can adapt it to the desired aim. The prior art usable by thenormally skilled worker in order to establish conditions for thepreparation of reagents can be found in numerous general chemistry textbooks such as “Advanced Organic Chemistry” by J. March, published byWiley (1992), “Methoden der organischen Chemie” (Houben-Weyl), publishedby Georg Thieme Verlag or the “Chemical Abstracts” published by theAmerican Chemical Society as well as in information data basesaccessible to the public.

[0137] The reactants in the above process are commercially available orreadily available utilising standard procedures.

[0138] The heterocyclic acids of general formula (a) may be obtained inthe form of their alkylesters. In this case, the compounds aresaponified according to standard deprotection procedures as described byor referenced in T. W. Greene, P. W. Greene, “Protective Groups inOrganic Synthesis”, Wiley & Sons, New York 1991. Subsequently, theheterocyclic acid or an acid derivative obtained from the acid isreacted with an amine according to known coupling procedures aspublished in Houben-Weyl, “Methoden der Organischen Chemie”, EugenMüller (Ed.), Thieme Publisher, Stuttgart. Subsequently, somesubstituants on the heterocylic carboxamide may optionally be subjectedto functional group transformations as described or referenced in R. C.Larock, “Comprehensive Organic Transformations”, VCH Publishers,Weinheim, 1989 or in computerised reaction databases like e.g.“Beilstein Commander 2000, Version 5.0”, provided by MDL databases, togive another compound of the general formula (I).

[0139] The present invention also relates to fungicidal compositioncomprising an effective amount of an active material of general formula(I). Thus, according to the present invention, there is provided afungicidal composition comprising, as an active ingredient, an effectiveamount of a compound of general formula (I) as defined above and anagriculturally acceptable support.

[0140] In the present specification, the term “support” denotes anatural or synthetic, organic or inorganic material with which theactive material is combined to make it easier to apply to the parts ofthe plant. This support is thus generally inert and should beagriculturally acceptable. The support may be a solid or a liquid.Examples of suitable supports include clays, natural or syntheticsilicates, silica, resins, waxes, solid fertilisers, water, alcohols, inparticular butanol, organic solvents, mineral and plant oils andderivatives thereof. Mixtures of such supports may also be used.

[0141] The composition may also comprise additional components. Inparticular, the composition may further comprise a surfactant. Thesurfactant can be an emulsifier, a dispersing agent or a wetting agentof ionic or non-ionic type or a mixture of such surfactants. Mention maybe made, for example, of polyacrylic acid salts, lignosulphonic acidsalts, phenolsulphonic or naphthalenesulphonic acid salts,polycondensates of ethylene oxide with fatty alcohols or with fattyacids or with fatty amines, substituted phenols (in particularalkylphenols or arylphenols), salts of sulphosuccinic acid esters,taurine derivatives (in particular alkyl taurates), phosphoric esters ofpolyoxyethylated alcohols or phenols, fatty acid esters of polyols, andderivatives of the above compounds containing sulphate, sulphonate andphosphate functions. The presence of at least one surfactant isgenerally essential when the active material and/or the inert supportare water-insoluble and when the vector agent for the application iswater. Preferably, surfactant content may be between 5% and 40% byweight.

[0142] Additional but optional components also include protectivecolloids, adhesives, thickeners, thixotropic agents, penetration agents,stabilisers, sequestering agents. More generally, the active materialscan be combined with any solid or liquid additive, which complies withthe usual formulation techniques.

[0143] In general, the composition according to the invention usuallymay contain from 0.05 to 99% (by weight) of active material, preferably10 to 70% by weight.

[0144] Compositions according to the present invention can be used inquite diverse forms such as aerosol dispenser, bait(ready for use), baitconcentrate, block bait, capsule suspension, cold fogging concentrate,dustable powder, emulsifiable concentrate, emulsion oil in water,emulsion water in oil, encapsulated granule, fine granule, flowableconcentrate for seed treatment, gas (under pressure), gas generatingproduct, grain bait, granular bait, granule, hot fogging concentrate,macrogranule, microgranule, oil dispersible powder, oil miscibleflowable concentrate, oil miscible liquid, paste, plant rodlet, platebait, powder for dry seed treatment, scrap bait, seed coated with apesticide, smoke candle, smoke cartridge, smoke generator, smoke pellet,smoke rodlet, smoke tablet, smoke tin, soluble concentrate, solublepowder, solution for seed treatment, suspension concentrate (flowableconcentrate), tracking powder, ultra low volume (ulv) liquid, ultra lowvolume (ulv) suspension, vapour releasing product, water dispersiblegranules or tablets, water dispersible powder for slurry treatment,water soluble granules or tablets, water soluble powder for seedtreatment and wettable powder.

[0145] These compositions include not only compositions which are readyto be applied to the plant or seed to be treated by means of a suitabledevice, such as a spraying or dusting device, but also concentratedcommercial compositions which must be diluted before they are applied tothe crop.

[0146] The compounds of the invention can also be mixed with one or moreinsecticides, fungicides, bactericides, attractant acaricides orpheromones or other compounds with biological activity. The mixturesthus obtained have a broadened spectrum of activity. In particular thecompounds of the present invention do not exhibit the problem ofcross-resistance with strobilurin derivatives. In fact the compounds ofthe present invention are active on a different biochemical site tostrobilurin derivatives.

[0147] The mixtures with other fungicides are particularly advantageous,especially the mixtures with acibenzolar-S-methyl, benalaxyl, benomyl,blasticidin-S, bromuconazole, captafol, captan, carbendazim, carboxin,carpropamide, chlorothalonil, fungicidal compositions based on copper,derivatives of copper such as copper hydroxide and copper oxychloride,cyazofamide, cymoxanil, cyproconazole, cyprodinil, dichloran,diclocymet, diethofencarb, difenoconazole, diflumetorim, dimethomorph,diniconazole, dodemorph, dodine, edifenphos, epoxyconazole, ethaboxam,ethirimol, famoxadone, fenamidone, fenarimol, fenbuconazole,fenhexamide, fenpiclonil, fenpropidine, fenpropimorph, ferimzone,fluazinam, fludioxonil, flumetover, fluquinconazole, flusilazole,flusulfamide, flutolanil, flutriafol, folpel, furalaxyl, furametpyr,guazatine, hexaconazole, hymexazol, imazalil, iprobenphos, iprodione,isoprothiolane, kasugamycin, mancozeb, maneb, mefenoxam, mepanipyrim,metalaxyl and their enantiomeric forms such as metalaxyl-M, metconazole,metiram-zinc, oxadixyl, pefirazoate, penconazole, pencycuron,phosphorous acid and its derivatives such as fosetyl-Al, phthalide,probenazole, prochloraz, procymidone, propamocarb, propiconazole,pyrimethanil, pyroquilon, quinoxyfen, silthiofam, simeconazole,spiroxamine, tebuconazole, tetraconazole, thiabendazole, thifluzarnide,thiophanate, for example thiophanate-methyl, thiram, triadimefon,triadimenol, triazolopyrimidines e.g. cloransulam-methyl, flumetsulam,florasulam, metosulam, tricyclazole, tridemorph, trifloxystrobin,triticonazole, derivatives of valinamide such as for example,iprovalicarb and benthiavalicarb, vinclozolin, zineb and zoxamide, aswell as fungicide of the strobilurin familly, for example azoxystrobin,kresoxym-methyl, metominostrobin, discostrobin, dimoxystrobin,picoxystrobin, pyraclostrobin, and trifloxystrobin.

[0148] The fungicidal compositions of the present invention can be usedto curatively or preventively combat the phytopathogenic fungi of crops.Thus, according to a further aspect of the present invention, there isprovided a method for curatively or preventively combating thephytopathogenic fungi of crops characterised in that a fungicidalcomposition as hereinbefore defined is applied to the seed, the plantand/or to the fruit of the plant or to the soil in which the plant isgrowing or in which it is desired to grow.

[0149] The composition as used against phytopathogenic fungi of cropscomprises an effective and non-phytotoxic amount of an active materialof general formula (I).

[0150] The expression “effective and non-phytotoxic amount” means anamount of composition according to the invention which is sufficient tocontrol or destroy the fungi present or liable to appear on the crops,and which does not entail any appreciable symptom of phytotoxicity forthe said crops. Such an amount can vary within a wide range depending onthe fungus to be combated, the type of crop, the climatic conditions andthe compounds included in the fungicidal composition according to theinvention.

[0151] This amount can be determined by systematic field trials, whichare within the capabilities of a person skilled in the art.

[0152] The method of treatment according to the present invention isuseful to treat propagation material such as tubers and rhizomes, butalso seeds, seedlings or seedlings pricking out and plants or plantspricking out. This method of treatment can also be useful to treatroots. The method of treatment according to the present invention canalso be useful to treat the overground parts of the plant such astrunks, stems or stalks, leaves, flowers and fruits of the concernedplant.

[0153] Among the plants targeted by the method according to theinvention, mention may be made of cotton; flax; vine; fruit crops suchas Rosaceae sp. (for instance pip fruits such as apples and pears, butalso stone fruits such as apricots, almonds and peaches), Ribesioidaesp., Juglandaceae sp., Betulaceae sp., Anacardiaceae sp., Fagaceae sp.,Moraceae sp., Oleaceae sp., Actinidaceae sp., Lauraceae sp., Musaceaesp. (for instance banana trees and plantins), Rubiaceae sp., Theaceaesp., Sterculiceae sp., Rutaceae sp. (for instance lemons, oranges andgrapefruits); leguminous crops such as Solanaceae sp. (for instancetomatoes), Liliaceae. sp., Asteraceae sp. (for instance lettuces),Umbelliferae sp., Cruciferae sp., Chenopodiaceae sp., Cucurbitaceae sp.,Papilionaceae sp. (for instance peas), Rosaceae sp. (for instancestrawberries); big crops such as Graminae sp. (for instance maize,cereals such as wheat, rice, barley and triticale), Asteraceae sp. (forinstance sunflower), Cruciferae sp. (for instance colza), Papilionaceaesp. (for instance soja), Solanaceae sp. (for instance potatoes),Chenopodiaceae sp. (for instance beetroots); horticultural and forestcrops; as well as genetically modified homologues of these crops.

[0154] Among the plants and the possible diseases of these plantstargeted by the method according to the present invention, mention maybe made of:

[0155] wheat, as regards controlling the following seed diseases:fusaria (Microdochium nivale and Fusarium roseum), stinking smut(Tilletia caries, Tilletia controversa or Tilletia indica), septoriadisease (Septoria nodorum) and loose smut;

[0156] wheat, as regards controlling the following diseases of theaerial parts of the plant: cereal eyespot (Tapesia yallundae, Tapesiaacuiformis), take-all (Gaeumannomyces graminis), foot blight (F.culmorum, F. graminearum), black speck (Rhizoctonia cerealis), powderymildew (Erysiphe graminis forma specie tritici), rusts (Pucciniastrhiformis and Puccinia recondita) and septoria diseases (Septoriatritici and Septoria nodorum);

[0157] wheat and barley, as regards controlling bacterial and viraldiseases, for example barley yellow mosaic;

[0158] barley, as regards controlling the following seed diseases: netblotch (Pyrenophora graminea, Pyrenophora teres and Cochliobolussativus), loose smut (Ustilago nuda) and fusaria (Microdochium nivaleand Fusarium roseum);

[0159] barley, as regards controlling the following diseases of theaerial parts of the plant: cereal eyespot (Tapesia yallundae), netblotch (Pyrenophora teres and Cochliobolus sativus), powdery mildew(Erysiphe graminis forma specie hordei), dwarf leaf rust (Pucciniahordei) and leaf blotch (Rhynchosporium secalis);

[0160] potato, as regards controlling tuber diseases (in particularHeiminthosporium solani, Phoma tuberosa, Rhizoctonia solani, Fusariumsolani), mildew (Phytopthora infestans) and certain viruses (virus Y);

[0161] potato, as regards controlling the following foliage diseases:early blight (Alternaria solani), mildew (Phytophthora infestans);

[0162] cotton, as regards controlling the following diseases of youngplants grown from seeds: damping-off and collar rot (Rhizoctonia solani,Fusarium oxysporum) and black root rot (Thielaviopsis basicola);

[0163] protein yielding crops, for example peas, as regards controllingthe following seed diseases: anthracnose (Ascochyta pisi, Mycosphaerellapinodes), fusaria (Fusarium oxysporum), grey mould (Botrytis cinerea)and mildew (Peronospora pisi);

[0164] oil-bearing crops, for example rape, as regards controlling thefollowing seed diseases: Phoma lingam, Alternaria brassicae andSclerotinia sclerotiorum;

[0165] corn, as regards controlling seed diseases: (Rhizopus sp.,Penicillium sp., Trichoderma sp., Aspergillus sp., and Gibberellafujikuroi);

[0166] flax, as regards controlling the seed disease: Alternarialinicola;

[0167] forest trees, as regards controlling damping-off (Fusariumoxysporum, Rhizoctonia solani);

[0168] rice, as regards controlling the following diseases of the aerialparts: blast disease (Magnaporthe grisea), bordered sheath spot(Rhizoctonia solani);

[0169] leguminous crops, as regards controlling the following diseasesof seeds or of young plants grown from seeds: darnping-off and collarrot (Fusarium oxysporum, Fusarium roseum, Rhizoctonia solani, Pythiumsp.);

[0170] leguminous crops, as regards controlling the following diseasesof the aerial parts: grey mould (Botrytis sp.), powdery mildews (inparticular Erysiphe cichoracearum, Sphaerotheca fuliginea and Leveillulataurica), fusaria (Fusarium oxysporum, Fusarium roseum), leaf spot(Cladosporium sp.), altermaria leaf spot (Alternaria sp.), anthracnose(Colletoirichum sp.), septoria leaf spot (Septoria sp.), black speck(Rhizoctonia solani), mildews (for example Bremia lactucae, Peronosporasp., Pseudoperonospora sp., Phytophihora sp.);

[0171] fruit trees, as regards diseases of the aerial parts: moniliadisease (Monilia fructigenae, M. laxa), scab (Venturia inaequalis),powdery mildew (Podosphaera leucotricha);

[0172] vine, as regards diseases of the foliage: in particular greymould (Botrytis cinerea), powdery mildew (Uncinula necator), black rot(Guignardia biwelli) and mildew (Plasmopara viticola);

[0173] beetroot, as regards the following diseases of the aerial parts:cercospora blight (Cercospora beticola), powdery mildew (Erysiphebeticola), leaf spot (Ramularia beticola).

[0174] Cereals are preferably treated according to the method of thepresent invention. Wheat and rice are still preferred for carrying outthe method according to the invention.

[0175] The fungicide composition according to the present invention mayalso be used against fungal diseases liable to grow on or inside lumber.The term “lumber” means all types of species of wood, and all types ofworking of this wood intended for construction, for example solid wood,high-density wood, laminated wood, and plywood. The method for treatinglumber according to the invention consists in placing one or morecompounds of the present invention, or a composition according to theinvention, in contact. This placing in contact may cover the mostdiverse of forms such as, for example, direct application, spraying,dipping, injection or any other suitable means.

[0176] The dose of active material applied in the treatment according tothe present invention is generally and advantageously between 10 and 800g/ha, preferably between 50 and 300 g/ha for applications in foliartreatment. The dose of active material applied is generally andadvantageously between 2 and 200 g per 100 kg of seed, preferablybetween 3 and 150 g per 100 kg of seed in the case of seed treatments.It is clearly understood that the doses indicated above are given asillustrative examples of the invention. A person skilled in the art willknow how to tailor the application doses according to the nature of thecrop to be treated.

[0177] The fungicidal composition according to the present invention mayalso be used in the treatment of genetically modified plants with thecompounds according to the invention or the agrochemical compositionsaccording to the invention. Genetically modified plants are plants intowhose genome a heterologous gene encoding a protein of interest has beenstably integrated. The expression “heterologous gene encoding a proteinof interest” essentially means genes which give the transformed plantnew agronomic properties, or genes for improving the agronomic qualityof the transformed plant.

[0178] Among the genes which give the transformed plants new agronomicproperties, mention may be made of genes which impart a tolerance tocertain herbicides, those which impart a resistance to certain insects,those which impart a tolerance to certain diseases, etc. Such genes aredescribed in particular in patent applications WO 91/02071 and WO95/06128.

[0179] Among the genes which impart a tolerance to certain herbicides,mention may be made of the Bar gene imparting tolerance to bialophos,the gene encoding a suitable EPSPS imparting a resistance to herbicideshaving EPSPS as target, such as glyphosate and its salts (U.S. Pat. No.4,535,060, U.S. Pat. No. 4,769,061, U.S. Pat. No. 5,094,945, U.S. Pat.No. 4,940,835, U.S. Pat. No. 5,188,642, U.S. Pat. No. 4,971,908, U.S.Pat. No. 5,145,783, U.S. Pat. No 5,310,667, U.S. Pat. No. 5,312,910,U.S. Pat. No. 5,627,061, U.S. Pat. No. 5,633,435 and FR 2 736 926), thegene encoding glyphosate oxidoreductase (U.S. Pat. No. 5,463,175) or agene encoding an HPPD imparting a tolerance to herbicides having HPPD astarget, such as isoxazoles, in particular isoxafutol (FR 95/06800 and FR95/13570), diketonitriles (EP-A-0 496 630 and EP-A-0 496 631) ortriketones, in particular sulcotrioine (EP-A-0 625 505, EP-A-0 625 508and U.S. Pat. No. 5,506,195). Such genes encoding an HPPD imparting atolerance to herbicides having HPPD as target are disclosed in patentapplication WO 96/38567. In the case of genes encoding EPSPS or HPPD,and more particularly for the above genes, the sequence encoding theseenzymes is advantageously preceded by a sequence encoding a transitpeptide, in particular for the transit peptide known as optimizedtransit peptide, disclosed in patent U.S. Pat. No. 5,510,471.

[0180] Among the genes imparting novel insect-resistance properties,mention will be made more particularly of the genes encoding the Btproteins which are widely described in the literature and well known tothose skilled in the art. Mention will also be made of the genesencoding proteins extracted from bacteria such as Photorabdus (WO97/17432 and WO 98/08932).

[0181] Among the genes imparting novel disease-resistance properties,mention will be made in particular of the genes encoding chitinases,glucanases and oxalate oxidase, all these proteins and their codingsequences being widely described in the literature, or genes encodingantibacterial and/or antifungal peptides, in particular cysteine-richpeptides containing less than 100 amino acids, such as plant thioninesor defensines, and more particularly lytic peptides of all originscomprising one or more disulphide bridges between the cysteines andregions comprising basic amino acids, in particular the following lyticpeptides: androctonine (WO 97/30082 and PCT/FR98/01814, filed on 18August 1998) or drosomicin (PCT/FR98/01462, filed on 8 Jul. 1998).Mention will also be made of the genes encoding fungal elicitorpeptides, in particular the elicitins (Kamoun et al., 1993; Panabièreset al., 1995).

[0182] Among the genes which modify the constitution of modified plants,mention may be made in particular of genes which modify the content andquality of certain essential fatty acids (EP-A-0 666 918) or the contentand quality of proteins, in particular in the leaves and/or seeds of thesaid plants. Mention will be made in particular of the genes encodingproteins that are rich in sulphur-containing amino acids (WO 98/20133;WO 97/41239; WO 95/31554; WO 94/20828 and WO 92/14822).

[0183] The fungicidal composition according to the present inventionmay, in particular, be used to the treatment of genetically modifiedplants comprising a heterologous gene, which gives the plantdisease-resistance properties. The heterologous gene preferentiallygives the genetically modified plant a spectrum of activity that iscomplementary to the spectrum of activity of the compounds according tothe invention. According to the invention, the expression “complementaryspectrum” means a spectrum of activity for the heterologous gene whichis different from the spectrum of activity of the compounds according tothe invention, or a spectrum of activity relating to identicalinfectious agents but allowing an identical or improved control forlower application doses of compounds according to the invention.

[0184] The compositions according to the present invention may also beused used to curatively or preventively treat human and animal fungaldiseases such as, for example, mycoses, dermatoses, trichophytondiseases and candidiases or diseases caused by Aspergillus spp., forexample Aspergillus fumigatus.

[0185] The aspects of the present invention will now be illustrated withreference to the following tables of compounds and examples. Thefollowing Tables I to XII illustrate in a non-limiting manner examplesof fungicidal compounds according to the present invention. In thefollowing Examples, “MP” signifies “melting point” and is expressed in °Celsius (° C.). M+1 (or M−1) means the molecular ion peak, plus or minus1 a.m.u. (atomic mass units) respectively, as observed in massspectroscopy. TABLE I THIOPHENE DERIVATIVES

N^(o) X1 Y G Z Q1 1

—O—

2

—O—

3

—O—

4

—O—

N^(o) T Q2 ion mol. MP 1 —O—

M + 1 = 395 2 —O—

M + 1 = 493 3 —O—

M + 1 = 438 4 —O—

M + 1 = 472

[0186] TABLE II PYRROLE DERIVATIVES

N^(o) X2 X1 Y G Z Q1 5

—O—

6

—O—

7

—O—

8

—O—

9

—O—

N^(o) T Q2 ion mol. MP 5 —O—

M + 1 = 490 6 —O—

M + 1 = 490 7 —O—

M + 1 = 478 8 —O—

M + 1 = 402 9 —O—

M + 1 = 304

[0187] TABLE III PYRROLE DERIVATIVES

N^(o) X2 X1 Y G Z Q1 10

—O—

11

—O—

12

—O—

13

—O—

14

—O—

15

—O—

16

—O—

17

—O—

18

—O—

N^(o) T Q2 ion mol. MP 10

M + 1 = 289 11 —O—

M + 1 = 319 12 —O—

M + 1 = 463 13 —O—

M + 1 = 435 14 —O—

M + 1 = 406 15 —O—

M + 1 = 449 16 —O—

M + 1 = 361 17 —O—

M + 1 = 375 18 —O—

M + 1 = 347

[0188] TABLE IV PYRIDINE DERIVATIVES

N^(o) X1 X2 Y G Z Q1 19

—O—

20

—O—

21

—O—

22

—O—

23

—O—

24

—O—

25

—O—

26

—O—

27

—O—

N^(o) T Q2 ion mol. MP 19 —O—

M − 1 = 388 20 —O—

M + 1 = 302 21

M + 1 = 278 22 —O—

M + 1 = 336 23 —O—

M + 1 = 390 24 —O—

M + 1 = 424 25 —O—

26 —O—

27 —O—

M + 1 = 346

[0189] TABLE V ISOXAZOLE DERIVATIVES

N^(o) Y G Z Q1 T Q2 ion mol. MP 28

—O—

—O—

M + 1 =452 29

—O—

—O—

M + 1 =452 30

—O—

M + 1 =368 172 31

—O—

M + 1 =296 208 32

—O—

—O—

M + 1 =380 33

—O—

—O—

M + 1 =432 34

—O—

M + 1 =340 35

—O—

—O—

M + 1 =374 36

—O—

M + 1 =282 37

—O—

M + 1 =310 38

—O—

M + 1 =268

[0190] TABLE VI ISOXAZOLE DERIVATIVES

N^(o) Y G Z Q1 T Q2 ion mol. MP 39

—O—

—O—

M + 1 = 437 40

—O—

—O—

M + 1 = 423 41

—O—

—O—

M + 1 = 349

[0191] TABLE VII ISOTHIAZOLE DERIVATIVES

N^(o) Y G Z Q1 T Q2 ion mol. MP 42

bond

—O—

M + 1 = 380

[0192] TABLE VIII PYRAZOLE DERIVATIVES

N^(o) X1 Y G Z Q1 T Q2 ion mol. MP 43

—O—

—O—

M + 1 = 393 44

—O—

—O—

M + 1 = 393 134

[0193] TABLE IX PYRIDINE DERIVATIVES N^(o) X1 X2 Y G Z Q1 45

—O—

46

—O—

47

—O—

48

—O—

49

—O—

50

—O—

51

—O—

52

—O—

53

—O—

54

—O—

55

—O—

56

—O—

57

—O—

58

—O—

N^(o) T Q2 ion mol. MP 45 —O—

M + 1 = 388 166 46 —O—

M + 1 = 390 186 47 —O—

M + 1 = 418 48

M + 1 = 402 200 49 —O—

M + 1 = 481 164 50 —O—

M + 1 = 466 218 51

M + 1 = 430 232 52 —O—

M + 1 = 336 53 —O—

M + 1 = 374 236 54 —O—

M + 1 = 452 55 —O—

M + 1 = 424 56 —O—

M + 1 = 476 57 —O—

M + 1 = 384 58 —O—

M + 1 = 462

[0194] TABLE X PYRANONE DERIVATIVES

N^(o) X1 X2 Y G Z Q1 59

—O—

60

—O—

61

—O—

62

—O—

63

—O—

64

—O—

65

—O—

66

—O—

67

—O—

68

—O—

69

—O—

70

—O—

71

—O—

N^(o) T Q2 ion mol. MP 59 —O—

203-204 60 —O—

203 61 —O—

62 —O—

63 —O—

64

65 —S—

66 —O—

67 —O—

68 —O—

69

70 —O—

71 —O—

228

[0195] TABLE XI PYRROLIDINE DERIVATIVES

ion N° X1 X2 Y G Z Q1 T Q2 mol. MP 72

—O—

—O—

251 73

—O—

—O—

M +1 =421

[0196] TABLE XII PYRIDAZINE DERIVATIVES

N° X1 Y G Z Q1 T Q2 ion mol. MP 74

—O—

—O—

75

—O—

—O—

Examples of Process for Preparation of the Compounds of General Formula(I) EXAMPLE 1 Preparation of pyrrole-2-carboxamides of Formula (I)Preparation of Starting Materials 4-(4-Trifluormethylphenoxy)aniline

[0197]

[0198] To a stirred solution of 4-trifluormethylbromobenzene (11.2 g, 50mmol) in dimethylsulphoxide (50 mL) is added powdered potassiumcarbonate (3.4 g, 60 mmol) and 4-aAminophenol (6.6 g, 55 mmol). Thesuspension is heated at 90° C. for 4.5 h, then poured into water,extracted with di-isopropylether, filtered, decanted, the organic phasewashed with water, dried (magnesium sulphate) and evaporated to give 9.6g of a brown oil. To this triturated with pentane, the resultingprecipitate is filtered, washed with pentane and dried to give 3.3 g ofthe title compound (27%, mp. 72° C.).

1-Methyl-4-[(allyloxycarbonyl)amino]-3-methoxy-1H-pyrrole-2-carboxylicacid

[0199]

[0200] A mixture of 0.93 g (3.3 mmol) of ethyl1-methyl-4-[(allyloxycarbonyl)amino]-3-methoxy-1H-pyrrole-2-carboxylate(prepared according to the method described in K. Narkunan, M. A.Ciufolini, Synthesis, 2000, 673-676), 3.3 ml of a 2 molar sodiumhydroxide aqueous solution and 3.3 ml of ethanol is stirred at roomtemperature for 5 days. Water is added and the ethanol is evaporated.After extraction with diethyl ether, the aqueous phase is acidified topH 2 with concentrated hydrochloric acid. Extraction with ethyl acetate,drying and concentration give 0.6 g (71% yield) of a light brown solid.(M−1=253).

Coupling Procedure According to Scheme 1 1-Methyl-4-[(allyloxycarbonyl)amino]-3-methoxy-1H—N-para-[4-(trifluoromethyl)phenoxy]phenyl-pyrrole-2-carboxamide(5)

[0201]

[0202] A mixture of 0.127 g (0.5 mmol) of 1-methyl-4-[(allyloxycarbonyl)amino]-3-methoxy-pyrrole-2-carboxylic acid, 0.127 g (0.5 mmol) of4-[4-(trifluoromethyl) phenoxy]aniline, and 0.105 g (0.55 mmol) of1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride in 2.5 mlof pyridine is heated at 90° C. for 3 hours. After cooling, the pyridineis evaporated, the resulting dark oil is stirred at 0° C. with 10 ml ofa 15% hydrochloric acid solution for 0.5 hour. The resulting precipitateis filtered off and washed with water and with diethyl ether. The solidis chromatographed (ethyl acetate/heptane) to give 0.08 g (33% yield) ofa white solid (MP=144° C.).

Functional group transformation according to Scheme 1:1-Methyl-4-amino-3-hydroxy-1H—N-(4-butoxy-phenyl) pyrrole-2-carboxamide(9)

[0203]

[0204] To 0.361 g (0.9 mmol) of 1-Methyl-4-[(allyloxycarbonyl)amino]-3-methoxy-1H—N-(4-butoxy phenyl)-pyrrole-2-carboxamide in 9 ml ofdichloromethane at −5° C., 2 ml (2.1 mmol) of a 1 molar solution ofboron tribromide in dichloromethane is added drop-wise. The mixture isstirred for 4 hours with the temperature being kept between 0 and 10°C., then for 20 hours at room temperature. The reaction mixture ispoured into a mixture of saturated solution of sodium hydrogenocarbonateand ethyl acetate, The precipitate obtained is filtered off and washedwith diethyl ether. There is obtained 0.100 g of a solid (M+1=304).

EXAMPLE 2 Preparation of pyrrole-3-carboxamides of Formula (I) CouplingProcedure According to Scheme 11-methyl-2-ethoxycarbonyl-3-hydroxy-1H—N-para-[4-(trifluoromethyl)phenoxy]phenyl-pyrrole-4-carboxamide (15)

[0205]

[0206] To a mixture of 1.0 g (4.69 mmol) of1-methyl-2-ethoxycarbonyl-3-hydroxy-1H-pyrrole-4-carboxylic acid(prepared according to the method described in K. Narkunan, M. A.Ciufolini, Synthesis, 2000, 673-676), 1.42 g (5.63 mmol) of4-[4-(trifluoromethyl) phenoxy]aniline, and 0.644 g (4.69 mmol) of1-hydroxy benzotriazol in 10 ml of tetrahydrofuran cooled to 0° C. isadded 1.08 g (5.63 mmol) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 10 ml oftetrahydrofuran. The resulting mixture is stirred at 0° C. for 2 hoursand then heated at 45° C. for 16 hours. After cooling, thetetrahydrofuran is evaporated. The residue is chromatographed (ethylacetate/heptane 9/1 to 6/4) to give 1.37 g (65% yield) of a yellow solid(M+1=449)

Functional Group Transformation According to Scheme 11-methyl-2-ethoxycarbonyl-3-methoxy-1H—N-para-[4-(trifluoromethyl)phenoxy]phenyl-pyrrole-4-carboxamide (12)

[0207]

[0208] To a mixture of 0.80 g (1.78 mmol) of1-methyl-2-ethoxycarbonyl-3-hydroxy-1H—N-para-[4-(trifluoromethyl)phenoxy]phenyl-pyrrole-4-carboxamide,0.49 g (3.57 mmol) of potassium carbonate in 8 ml of acetone undernitrogen, is added 0.20 mL (2.14 mmol) of dimethylsulphate. Theresulting mixture is stirred at 50° C. for 16 hours. Afterconcentration, the residue is taken up in water. Extraction with diethylether and ethyl acetate, drying, and concentration give 0.745 g (90%yield) of an orange oil (M+1=463)

1-methyl-2-hydroxycarbonyl-3-methoxy-1H—N-para-[4-(trifluoromethyl)phenoxy]phenyl-pyrrole-4-carboxamide (13)

[0209]

[0210] To a solution of 0.64 g (1.39 mmol) of1-methyl-2-ethoxycarbonyl-3-methoxy-1H—N-para-[4-(trifluoromethyl)phenoxy]phenyl-pyrrole-4-carboxamidein 4 ml of ethanol is added 1.4 ml (2.8 mmol) of a 2 molar sodiumhydroxide solution. The resulting solution is stirred at roomtemperature for 5 days. Water is added and the ethanol is evaporated.After extraction with diethyl ether, the aqueous phase is acidified topH 2 with concentrated hydrochloric acid. Extraction with ethyl acetate,drying and concentration give 0.5 g (85% yield) of a yellowish solid.(M+1=435).

1-methyl-2-amino-3-methoxy-1H—N-para-[4-(trifluoromethyl)phenoxy]phenyl-pyrrole-4-carboxamide(14)

[0211]

[0212] 0.46 g (1.05 mmol) of1-methyl-2-hydroxycarbonyl-3-methoxy-1H—N-para-[4-(trifluoromethyl)phenoxy]phenyl-pyrrole-4-carboxamideis stirred at room temperature for 18 hours in 3.5 ml of thionylchloride. After concentration, the residue is taken up indi-isopropylether, and the suspension is filtered off. The filtrate isconcentrated to give 0.4 g (85% yield) of an orange solid. A solutioncontaining 0.370 g (0.82 mmol) of the obtained acid chloride in 12 ml ofacetone is added to a solution of 0.06 g (1 mmol) of sodium azide in 0.2ml of water. After 0.5 hours of stirring, 12 ml of water is added, andthe suspension is filtered off. The solid is washed with water andheptane. The filtrate's phases are separated and the aqueous phase ismade basic. Extraction with ethyl acetate, drying and concentration give0.13 mg (39% yield) of a yellow powder

EXAMPLE 3 Preparation of Pyrazoles of Formula (I) Coupling ProcedureAccording to Scheme 14-Bromo-1-methyl-5-nitro-N-para-[3-(trifluoromethyl)phenoxy]phenylpyrazole-3-carboxamide

[0213]

[0214] To a mixture of 0.99 g (3.96 mmol) of1-methyl-4-bromo-5-nitropyrazole-3-carboxylic acid (prepared accordingto the method described in Y. Manaev, M. Andrea, V. Perevalov, B.Stepanov, V. Dubrovskaya, V. Seraya, J. Gen. Chem. USSR (Engl. Trans.)1982, 2291-2296), 1.00 g (3.96 mmol) of 4-[3-(trifluoromethyl)phenoxy]aniline, and 0.05 g (0.39 mmol) of 1-hydroxybenzotriazole in 50ml of dichloromethane with ice cooling, is added 0.83 g (4.35 mmol) of1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride inportions. The resulting mixture is stirred at room temperature for 2hours, and diluted with 150 mL dichloromethane and 100 ml of a 1 molarhydrochloric acid solution. The two phases solution is well shaken, andthe phases are separated. The dichloromethylated solution is dried andconcentrated to give a yellow solid, which is washed with di-isopropylether to give 1.56 g (81% yield) of compound 70 as a solid (M+1=485).

Functional Group Transformation According to Scheme 11-Methyl-4-hydroxy-5-amino-N-para-[3-(trifluoromethyl) phenoxy] phenylpyrazole-3-carboxamide (44)

[0215]

[0216] A mixture of 1.5 g (3.1 mmol) of1-methyl-4-bromo-5-nitro-N-para-[3-(trifluoromethyl)phenoxy]phenylpyrazole-3-carboxamide, 2.5 g (0.065 mmol) of sodium hydroxide, 25 ml ofwater, 25 ml of ethanol and 200 mg (0.8 mmol) of copper bromide isstirred at 90° C. for 1 hour, 25 ml of water is added and the mixture isstirred at 100° C. for 3 hours. After cooling, the mixture is dilutedwith 200 ml of water and made acidic with concentrated hydrochloricacid. After extraction with ethyl acetate, drying and concentration to 5ml, diethyl ether is added and after 5 minutes of stirring, theresulting solid is filtered off and washed with more diethyl ether toprovide 0.54 g of a solid. Of this solid, 0.47 g (1.11 mmol) were mixedwith 0.10 g of 5% palladium on charcoal in 50 ml of methanol and stirredat room temperature under hydrogen at 60 psi for 3 hours. Filtrationthrough silica and washing with acetic acid, concentration give a greensolid which is washed with diethyl ether to give 0.15 g (34% yield) of71 as a grey solid (M+1=393).

EXAMPLE 4 Preparation of Isoxazoles of Formula (I) Preparation ofStarting Material3-(methoxycarbonyl)amino-4-methoxy-isoxazole-5-carboxylic acid

[0217]

[0218] A mixture of 2.50 g (0.011 mmol) ofmethyl-3-(methoxycarbonyl)amino-4-methoxy-isoxazole-5-carboxylate(prepared according to the method described in W. Kloetzer, J. Schantz,Monatsh. Chem., 1965, 102-115) and 1.30 g of powdered sodium hydroxidedissolved in 9 ml of water is heated at 90° C. for 3 hours. Aftercooling, the mixture is acidified to pH=2 with concentrated hydrochloricacid, controlling the temperature so as not to exceed 5° C. After 1 hourof stirring at 0° C., the precipitate obtained is filtered off andwashed with cold water. There is obtained 2.01 g (86% yield) of a whitesolid (M+1=217).

Coupling Procedure According to Scheme 13-[(Methoxycarbonyl)amino]-N-para-[4-(trifluoromethyl)phenoxy]phenyl-isoxazol-5-carboxamide(28)

[0219]

[0220] A mixture of 0.162 g (0.75 mmol) of3-(methoxycarbonyl)amino-4-methoxy-isoxazole-5-carboxylic acid, 0.172 g(0.68 mmol) of 4-[4-(trifluoromethyl) phenoxy]aniline and 0.212 g (0.75mmol) of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholiniumchloride in 5 ml of ethanol is heated at 70° C. for 6 hours, and thenstirred at room temperature for 16 hours. After evaporation of theethanol, the residue is taken up in ethyl acetate and the resultingsolution is washed successively with a saturated solution of sodiumhydrogenocarbonate, water, 2% solution of hydrochloric acid, and water.After drying and concentrating, the residue is chromatographed (ethylacetate/heptane, 2:8) to give 0.122 g (37% yield) of a cream solid(M+1=452).

Functional Group Transformation According to Scheme 13-Amino4-hydroxy-N-para-[4-(trifluoromethyl) phenoxy]phenylisoxazole-5-carboxamide (32)

[0221]

[0222] To 0.122 g (0.27 mmol) of3-[(methoxycarbonyl)amino]-N-para-[4-(trifluoromethyl)phenoxy]phenylisoxazole-5-carboxamide in 2 ml of dichloromethane at 0°C., 0.62 ml (0.62 mmol) of a 1 molar solution of boron tribromide indichloromethane is added drop-wise. The mixture is stirred for 4 hourswith the temperature being kept between 0 and 10° C., then for 20 hoursat room temperature. The reaction mixture is poured into a saturatedsolution of sodium hydrogenocarbonate, and the phases are separated. Theaqueous phase is further extracted with ethyl acetate. The combinedorganic phases are dried and concentrated. The residue is stirred inacetonitrile and the resulting suspension is filtered off to give acream solid.

EXAMPLE 5 Preparation of Isoxazole-3-carboxamides of Formula (I)Coupling Procedure According to Scheme 12-methoxycarbonyl-3-methoxy-N-para-[4-(trifluoromethyl)phenoxy]phenylisoxazole-4-carboxamide (39)

[0223]

[0224] To a suspension of 1 g (4.4 mmol) of2-azidocarbonyl-3-methoxy-isoxazole-4-carboxylic acid (preparedaccording to the method described in W. Kloetzer, J. Schantz, Monatsh.Chem., 1965, 102-115) in 10 ml of water cooled at 0° C., is addeddrop-wise a solution of 3.36 g (13.2 mmol) of4-[4-(trifluoromethyl)phenoxy]aniline in 15 ml of tetrahydrofuran. Theresulting mixture is stirred at 0° C. for 5 hours and left to stand atroom temperature for 16 hours. After concentration, the residue is takenup in ethyl acetate and the organic phase is washed successively with a1% hydrochloric acid solution, and with brine. Drying and concentrationgive a solid which is purified on silica to give 0.72 g (38% yield) of awhite solid (M+1=436).

Functional Group Transformation According to Scheme 12-hydroxycarbonyl-3-hydroxy-N-para-[4-(trifluoromethyl)phenoxy]phenyl-isoxazole-4-carboxamide (40)

[0225]

[0226] A mixture of 0.64 g (1.47 mmol) of2-methoxycarbonyl-3-methoxy-N-para-[4-(trifluoromethyl) phenoxy]phenyl-isoxazole-4-carboxamide, 0.98 g (7.4 mmol) of lithium iodide, and0.12 g (1.47 mmol) of sodium acetate in 5 ml of dimethyl-formamide isheated at 90° C. for 8 hours, left to stand at room temperature andheated at 90° C. for 6 hours. After cooling, 15 ml of water is added,the solution is made basic with a 30% sodium hydroxide solution andwashed 3 times with diethyl ether. The aqueous phase is acidified with aconcentrated hydrochloric acid solution. After extraction with ethylacetate, the organic phase is washed with a saturated lithium chloridesolution, dried, and concentrated to give 0.33 g (56% yield) of a solid.

EXAMPLE 6 Preparation of Pyridine-4-carboxamides of Formula (I)Preparation of Starting Material[(2-Diethylamino-oxazole[4,5-b3]pyridine]-4-carboxylic acid

[0227]

[0228] A solution oft-butyl-[(2-diethylamino-oxazolo[4,5-b3]pyridine]-4-carboxylate (0.76 g,2.61 mmol) was prepared as described in the literature (R. K. Russel etal., Tetrahedron Lett. 1993, 34, 203-206) and the crude materialrefluxed for 3 hours in formic acid (15 mL). Then all volatiles wereremoved, the residue taken up in trichloromethane out of which the purematerial precipitated upon cooling (577 mg, 94%). (M+1=236).

Coupling Procedure and Functional Group Transformation According toScheme 1[4-(Trifluoromethyl)phenoxy]anilino-(2-amino-3-hydroxy)pyridyl-4-carboxamide(19)

[0229]

[0230] To a mixture of[(2-diethylamino-oxazolo[4,5-b3]pyridine]-4-carboxylic acid (0.30 g,1.28 mmol), 4-dimethylaminopyridine (16 mg, 0.13 mmol) and4-(trifluoromethyl) phenoxy]anilin (0.39 g, 1.53 mmol) in pyridine (15mL) was added dimethylamino-propylethylcarbodiimide (0.28 g, 1.79 mmol).The reaction mixture was stirred for 3d, then all volatiles removed, thecrude taken up in ethylacetate, extracted with pH 4 buffer solution, theorganic phase separated, dried (magnesium sulphate), evaporated and theresidue purified by chromatography (silica, heptane/ethyl acetate) togive 256 mg of a yellow solid. 100 mg of this solid were dissolved indimethylsulphoxide (2 mL) to which was added 50% aqueous potassiumhydroxide (3 mL), the solution was stirred for 2 h at 80° C., thencooled to room temperature, poured into pH4 buffer solution andextracted with ethyl acetate. After drying the organic phase (magnesiumsulphate),evaporation of all volatiles and chromatography, 31 mg of thedesired product was obtained as yellow solid (38%). (M−1=388).

EXAMPLE 7 Preparation of Isothiazoles of Formula (I) Coupling ProcedureAccording to Scheme 15-Nitro-N-para-[4-(trifluoromethyl)phenoxy]phenyl-isothiazole-3-carboxamide(58)

[0231]

[0232] To 0.8 g (4.6 mmol) of 5-nitro-isothiazole-3-carboxylic acid(prepared according to the method described in R. J. A. Walsh, K. R. H.Woolbridge, J. Chem. Soc. Perkin Trans 1, 1972, 1247-1249) is added 14ml of thionyl chloride under nitrogen, and the resulting mixture isstirred at reflux for 3 hours. After cooling, the solvent is evaporatedto give a solid. This solid is suspended in a mixture of 20 ml ofdiethyl ether and 20 ml of dichloromethane. The suspension is added to amixture of 2.74 g (10.8 mmol) of 4-[4-(trifluoromethyl) phenoxy] anilineand 2.5 ml (18.3 mmol) of triethylamine in 40 ml of diethyl ether. Theresulting mixture is stirred at room temperature for 4 hours and left tostand at room temperature overnight. The resulting suspension isfiltered, the filtrate is washed with a saturated sodium chloridesolution, then dried and concentrated to give a brown solid which ischromatographed (ethyl acetate/heptane) to give 1.2 g (63% yield) of anorange solid (M+1=410).

Functional Group Transformation According to Scheme 15-Amino-N-para-[4-(trifluoromethyl)phenoxy]phenyl-isothiazole-3-carboxamide(42)

[0233]

[0234] To a solution of 1.05 g (2.57 mmol) of5-nitro-N-para-[4-(trifluoromethyl)phenoxy]phenyl-isothiazole-3-carboxamide in 5 ml of concentrated hydrochloricacid is added a solution of 2.5 g (12.8 mmol) of tin chloride in 5 ml ofconcentrated hydrochloric acid and the resulting mixture is heated at70° C. for 16 hours. After cooling, the solvent is evaporated, and theresidue is taken up in water. The aqueous phase is made basic with a 30%sodium hydroxide solution. After extraction with ethyl acetate, drying,and concentration, the residue is chromatographed (ethylacetate/heptane) to give 0.580 g (60% mmol) of a light brown solid(M+1=380).

EXAMPLE 8 Preparation of Thiophene-2-carboxamides of Formula (I)Coupling Procedure According to Scheme 14-Bromo-3-methoxy-N-4-[4(trifluoromethyl)phenoxy]phenyl-thiophene-2-carboxamide

[0235]

[0236] To 2.39 g (10 mmol) of 4-bromo-3-methoxy thiophene-2-carboxylicacid (prepared according to the method of C. Corral, M. B. El-Ashmawy,J. Lissavetzky, A. Basilio, A. Giraldez, Eur. J. Med. Chem. 1987, 22,251-254) was added 10 ml of thionyl chloride, the mixture was refluxedfor 2 hours, cooled to room temperature and the excess thionyl chlorideremoved by evaporation. The crude acid chloride in 10 ml of drytetrahydrofuran was added drop wise to a stirred mixture of 0.53 g (10mmol) of 4-(4-trifluorophenoxy)aniline and 1.01 g (10 mmol) oftriethylamine in 20 ml of dry tetrahydrofuran at 0° C., the mixturestirred at room temperature for 18 hours, treated with 150 mL of waterand extracted with diethyl ether, dried and evaporated to yield a solid,which was washed with pentane to yield 4.43 g (94% yield) of a buffsolid (M+1=473).

Functional Group Transformation According to Scheme 12-N-4-[4(Trifluoromethyl)phenoxy]phenylcarboxamide-3-methoxythiophene-4-carboxylic acid (3)

[0237]

[0238] To 2.00 g (4.24 mmol) of4-bromo-3-methoxy-N-4-[4-(trifluoromethyl)phenoxy]phenyl-thiophene-2-carboxamide in 40 ml of dry tetrahydrofuranat −78° C., was added drop-wise 6 ml (8.9 mmol) of n-butyllithium (1.6Min hexane) the reaction stirred at −78° C. for 1 hour before he mixturewas poured onto an excess of dry ice and allowed to warn to roomtemperature. After treatment with 50 mL of water and extraction withdiethyl ether, the aqueous fraction was acidified to pH3 with aqueoushydrogen chloride and extracted with dichloromethane, dried andevaporated to yield a solid, washed with 5% diethyl ether in pentane andfiltered to yield 1.11 g (54% yield) of a buff solid (M+1=438).

4-[(Allyloxycarbonyl)amino]-3-methoxy-N-4-[4-(trifluoromethyl)phenoxy]phenyl-thiophene-2-carboxamide(2)

[0239]

[0240] To 0.5 g (1.14 mmol) of 2-N-4-[4(trifluoromethyl)phenoxy]phenylcarboxamide-3-methoxy thiophene-4-carboxylic acid in 5 ml ofacetonitrile under argon was added 0.116 g (1.14 mmol) of triethylamineand 0.315 g (1.14 mmol) of diphenylphosphorylazide, the mixture washeated at 85° C. for 2 hours, 2.5 ml of allyl alcohol was added and theheating continued for 18 hours. The mixture was cooled to roomtemperature and evaporated, the residue was chromatographed(dichloromethane/heptane) to yield 0.15 g (27% yield) of a pale yellowsolid (M+1=493).

4-Methylthio-3-methoxy-N-4-[3-(trifluoromethyl)phenoxy]phenyl-thiophene-2-carboxamide(4)

[0241]

[0242] To 0.1 g (0.21 mmol) of 4-bromo-3-methoxy-N4-[3(trifluoromethyl)phenoxy]phenyl-thiophene-2-carboxamide in 2 ml of dry tetrahydrofuran,at −78° C., was added drop-wise 0.3 mL (0.45 mmol) of n-butyl lithium(1.6M in hexane). The mixture was stirred at −78° C. for 1 hour, treatedwith 0.02 g ((0.21 mmol) of dimethyl disulphide in 0.5 ml of drytetrahydrofuran, stirred at −78° C. for 3 hours and 18 hours at roomtemperature. The mixture was poured into 25 ml of water and extractedwith dichloromethane, dried and evaporated to yield an oil,chromatographed (dichloromethane/heptane) to yield 0.035 g (38% yield)of a colourless oil (M+1=440).

EXAMPLE 9 Preparation of Nicotinamide of Formula (I) Preparation ofStarting Materials 3-methyl-4-methoxy pyridine

[0243]

[0244] A mixture of 4 g (28.8 mmol) 3-methyl-4-methoxy pyridine N-oxide(prepared according to the method described in Kohl, Bernhard et al; J.Med. Chem.; 1992; 1049-1057) and 1.1 mg of 5% palladium on charcoal in50 ml of methanol is hydrogenated at 20 atms at room temperature for 12hours (2*6 hours). Filtration through celite, and evaporation gave 3.2 g(90%) of a light green oil.

3-methyl-4-methoxy-5-nitro pyridine

[0245]

[0246] 30 ml of 100% nitric acid is added to 150 ml of 98% sulphuricacid with stirring and cooling. To this solution is added dropwise 3.2 g(26 mmol) of 3-methyl-4-methoxy pyridine. The mixture is stirred at 80°C. for 2.5 hours, cooled down and added cautiously to a mixture of 400 gof crushed ice and 300 g of potassium carbonate with external cooling.125 g more of potassium carbonate is added, and the suspension isfiltered. The cake is washed with around 1 l of diethyl ether. Thefiltrate layers are separated, the ethereal layer is dried, filtered offand concentrated to give 2.9 g (30% yield) of a yellow oil (M+1 =169)(purity #80%, used with no further purification).

5-nitro-4-hydroxy-nicotinic acid

[0247]

[0248] 1.5 g (8.9 mmol) of 3-methyl-4-methoxy-5-nitro pyridine is addedwith stirring to 25 ml of ice cold concentrated sulphuric acid. 3.23 g(11.0 mmol) of potassium dichromate is added in portions over ¾hours,keeping the temperature between 45-55° C. Stirring is continued for ½hours, and the mixture is poured into 28 g of ice. Ph is adjusted to 1-2by addition of a 28% aqueous ammonium solution with cooling. Theprecipitate is filtered off and washed with small amount of very dilutedaqueous HCl. After drying, 0.95 g (58% yield) of a white solid (M+1=185)is obtained.

Coupling Procedure According to Scheme 15-nitro-4-hydroxy-N-para-[3-(trifluoromethyl) phenoxy]phenylnicotinamide

[0249]

[0250] A mixture of 400 mg (2.17 mmol) of 5-nitro-4-hydroxy-nicotinicacid, 2 drops of DMF and 20 ml of thionyl chloride is heated at 70° C.for 3 hrs. Thionyl chloride is removed under vacuum and the residue isdissolved in 15 ml of THF. To this solution is added a solution of 549mg (2.17 mmol) of para-[3-(trifluoromethyl) phenoxy] aniline and 438 mg(4.34 mmol) of triethylamine in 10 ml of THF. The resulting mixture isstirred for ½ hour at room temperature and added to dilute aqueous HCl.The aqueous phase is extracted with ethyl acetate. The combined organicphases are dried and concentrated. The residue is stirred in a solutionof 15 ml of methanol, 20 ml of water and 1 g of sodium hydroxide at 70°C. for 1 hrs and added to dilute aqueous HCl. The aqueous phase isextracted with ethyl acetate. The combined organic phases are dried andconcentrated to near dryness. Dilution with ether offered a solid whichwas filtered off and washed with ether. There is obtained 418 mg (44%yield) of a yellow solid (M−1=418).

Functional Group Transformation According to Scheme 15-amino-4-hydroxy-N-para-[3-(trifluoromethyl) phenoxy] phenylnicotinamide (45)

[0251]

[0252] A mixture of 200 mg (0.47 mmol) of5-nitro-4-hydroxy-N-para-[3-(trifluoromethyl) phenoxy] phenylnicotinamide and 100 mg of 5% palladium on charcoal in 30 ml of methanolis hydrogenated at 10 atms at room temperature for 2 hours. Filtrationthrough celite, and evaporation gave an oil. Trituration withdiisopropylether offered 125 mg (67% yield) of a grey solid (M−1=388)

EXAMPLE 10 Preparation of Nicotinamides of Formula (I) Preparation ofStarting Materials 2,6-dimethyl-4-hydroxy-nicotinic acid

[0253]

[0254] 10 g (59.5 mmol) of 2,6-dimethyl-4-oxo-4H-pyran-3-carboxylic acid(prepared according to the method described in Collie, J. Chem. Soc.;1907; 787) is stirred in 100 ml of 28% aqueous ammonia at roomtemperature overnight. The residue is diluted with little aqueous HCl,and the solid is filtered off. There is obtained 6.9 g (69% yield) of asolid.

2,6-dimethyl-5-nitro-4-hydroxy-nicotinic acid

[0255]

[0256] 20 ml of 90% nitric acid is added to 100 ml of 98% sulphuric acidwith stirring and cooling. To this solution is added portion-wise 6.9 g(41.1 mmol) of 2,6-dimethyl-4-hydroxy-nicotinic acid. The mixture isstirred at 80° C. for 1 hour, cooled down and added cautiously 300 g ofcrushed ice. The resulting suspension is filtered off. The cake iswashed with water and dried. There is obtained 6.7 g (77%) of a whitesolid.

Coupling Procedure According to Scheme 12,6-dimethyl-5-nitro-4-hydroxy-N-para-(1,1,2,2 tetrafluoroethoxy) phenylnicotinamlde

[0257]

[0258] A mixture of 1.0 g (4.7 mmol) of2,6-dimethyl-5-nitro-4-hydroxy-nicotinic acid in 20 ml of thionylchloride is heated at 70° C. for 3 hrs. Excess thionyl chloride isremoved under vacuum and the residue is suspended in 40 ml of THF. Tothis is added a solution of 0.99 g (4.7 mmol) of para (1,1,2,2tetrafluoroethoxy) aniline and 1 ml (7.1 mmol) of triethylamine in 10 mlof THF. The resulting mixture is stirred for ½ hour at room temperatureand the THF is removed under vacuum. The residue is partitioned betweenaqueous HCl and ethyl acetate. The organic phase is dried and filteredthrough silica. The filtrate is evaporated to give 1.53 g (80% yield) ofa pink solid (M+1=404).

Functional Group Transformation According to Scheme 12,6-dimethyl-5-amino-4-hydroxy-N-para-(1,1,2,2 tetrafluoroethoxy) phenylnicotinamide (53)

[0259]

[0260] A mixture of 1.4 g (3.47 mmol) of2,6-dimethyl-5-nitro-4-hydroxy-N-para-(1,1,2,2 tetrafluoroethoxy) phenylnicotinamide, 1.09 g (17.37 mmol) of ammonium acetate and 0.25 g of 10%palladium on charcoal in 80 ml of methanol is stirred at 70° C. for 3hours and filtered through celite. Methanol is evaporated and theresidue is partitioned between water and ethyl acetate. The phases areseparated and the organic layer is dried and evaporated. The residue iswashed with diisopropyl ether, filtered off and dried. There is obtained0.96 g (74% yield) of a yellow solid (M+1=374).

2,6-dimethyl-5-(2,5-dimethyl-pyrrol-1-yl)-4-hydroxy-N-para-(1,1,2,2tetrafluoroethoxy) phenyl nicotinamide (54)

[0261]

[0262] A mixture of 300 mg (0.8 mmol) of2,6-dimethyl-5-amino-4-hydroxy-N-para-(1,1,2,2 tetrafluoroethoxy) phenylnicotinamide and 183 mg (1.6 mmol) of acetonylacetone in 5 ml of aceticacid is heated at 70° C. for 15 minutes. The mixture is added to aqueousNaHCO₃, and extracted in ethyl acetate. The phases are separated and theorganic layer is dried and evaporated. The residue is washed withdiisopropyl ether, filtered off and dried. There is obtained 285 mg (79%yield) of a white solid (M+1=452).

2,6-dimethyl-5-pyrrol-1-yl-4-hydroxy-N-para-(1,1,2,2 tetrafluoroethoxy)phenyl nicotinamide (55)

[0263]

[0264] A mixture of 280 mg (0.75 mmol) of2,6-dimethyl-5-amino-4-hydroxy-N-para-(1,1,2,2 tetrafluoroethoxy) phenylnicotinamide and 132 mg (1.0 mmol) of 2,5-dimethoxy-tetrathydrofurane in6 ml of acetic acid is heated at 70° C. for 1 hour. The mixture is addedto aqueous NaHCO₃, and extracted in diethyl ether. The phases areseparated and the organic layer is dried and filtered through silica.The filtrate is evaporated. The residue is washed with diisopropylether, filtered off and dried. There is obtained 137 mg (43% yield) of awhite solid (M+1=424).

EXAMPLE 11 Preparation of Nicotinamides of Formula (I) Preparation ofStarting Materials Methyl-4-chloro-5-methoxycarbonyl-nicotinate

[0265]

[0266] A mixture of 16.38 g (77.6 mmol) of4-oxo-1,4-dihydro-pyridine-3,5-dicarboxylic acid dimethyl ester(prepared according to the method described in S. Zupancic,Heterocycles; 2000; 2033-2042) and 0.5 ml of DMF in 150 ml of thionylchloride is heated at reflux for 2 hours. Excess thionyl chloride isremoved under vacuum and the residue is added to aqueous NaHCO₃, andextracted in ethyl acetate. The phases are separated and the organiclayer is dried and evaporated. The residue is washed with aqueous K₂CO₃and water, and dried. There is obtained 7.35 g (41% yield) of whitesolid (M+1=230).

Methyl-4-methoxy-5-methoxycarbonyl-nicotinate

[0267]

[0268] To a solution of 6.3 g (27.5 mmol) ofmethyl-4-chloro-5-methoxycarbonyl-nicotinate in 100 ml of THF is added6.48 ml (35 mmol) of a 5.4 m solution of sodium methoxide in methanol.The mixture is stirred for 10 minutes and evaporated. 100 ml of a 0.25Maqueous HCl is added to the residue. The solution is made basic withK₂CO₃ and extracted with ethyl acetate. The organic phase is dried andevaporated to give an oil which crystallised on cooling. There isobtained 6.2 g (quantitative yield) of a solid (M+1=226).

4-methoxy-5-methoxycarbonyl-nicotinic acid

[0269]

[0270] To a solution of 5.3 g (23.5 mmol) ofmethyl-4-methoxy-5-methoxycarbonyl-nicotinate in 150 ml of methanol and50 m. of water is added a solution of 0.94 g (23.5 mmol) of sodiumhydroxide in 10 ml of water. The resulting mixture is stirred at roomtemperature overnight. The methanol is removed under vacuum, the aqueoussolution is made slightly acidic and extracted with ethyl acetate. Thecombined organic phases are dried and filtered through silica. Thefiltrate is evaporated to near dryness and diluted with diisopropylether. A precipitate is obtained, filtered off and dried. There isobtained 2.83 g (57% yield) of a white solid (M+1=212).

Coupling Procedure According to Scheme 15-methoxycarbonyl-4-methoxy-N-para-[3-chloro-4-(trifluoromethyl)phenoxy] phenyl nicotinamide (49)

[0271]

[0272] To a mixture of 0.68 g (2.37 mmol) of4-methoxy-5-methoxycarbonyl-nicotinic acid and 0.50 g (2.37 mmol) ofpara-[3-chloro-4-(trifluoromethyl) phenoxy] aniline in 25 ml ofdichloromethane is added 0.48 g (2.50 mmol) of 1-[3-(N,N-dimethyl-amino)propyl]-3-ethylcarbodiimide hydrochloride in one portion. The solutionis stirred at room temperature for 1 hour, and evaporated. The residueis taken up in a mixture of water, ethyl acetate, and 1 ml of 1M aqueousHCl. The organic layer is separated, dried and evaporated. The resultingsolid is washed with heptane/diisopropyl ether. There is obtained 0.70 g(61% yield) of a brown solid (M+1=481).

Functional Group Transformation According to Scheme 15-aminocarbonyl-4-methoxy-N-para-[3-chloro-4-(trifluoromethyl) phenoxy]phenyl nicotinamide (50)

[0273]

[0274] A mixture of 0.60 g (1.25 mmol) of5-methoxycarbonyl-4-methoxy-N-para-[3chloro-4-(trifluoromethyl) phenoxy]phenyl nicotinamide and 10 ml of a 7M solution of ammonia in methanol in30 ml of methanol is left to stand at room temperature for 3 days.Methanol is evaporated to near dryness (2 ml). The residue is dilutedwith diethyl ether. The resulting solid is filtered off and dried. Thereis obtained 0.207 g (35% yield) of a pink solid (M+1=466).

EXAMPLE 12 Preparation of γ-Pyronone-2-carboxamides of Formula (I)Preparation of Starting Materials

[0275] The starting material 2-Benzyloxy-γ-pyranon-2-carboxylic acid wasprepared according to known literature procedures; starting fromFurfurylalcohol 2-Hydroxy-methyl-pyromeconic acid was synthesized asdescribed by Z. D. Liu, H. H. Khodr. D. Y. Liu, S. L. Lu, R. C. Hider,J. Med. Chem. 1999, 42, 4814-4823. The subsequent benzylation was madeas described in Z. D. Liu, S. Piyamongkol, D. Y. Liu, H. H. Khodr, S. L.Lu, R. Hider, Bioorg. Med. Chem. 2001, 9, 563-574. The oxidation of the3-Benzyloxy-2-hydroxymethyl-γ-pyranon to2-Benzyloxy-γ-pyranon-2-carboxylic acid was executed as described by J.H. Looker, M. D. Cliffton, J. Heterocycl. Chem. 1986, 23, 225-227

Coupling Procedure According to Scheme 1N-(4-Butyloxy-phenyl)-2-(3-benzyloxy-γ-pyranone)-carboxamide

[0276]

[0277] To 2-Benzyloxy-γ-pyranon-2-carboxylic acid (0.5 g, 2 mmol) in drypyridine (10 mL) was added HOBt (0.27 g, 2 mmol), 4-Butoxyaniline (0.33g, 2 mmol) and EDCI (0.48 g, 2.5 mmol). The mixture was heated for 1 hat 85° C., then the pyridine evaporated, the residue dissolved andstirred for 15 min in a mixture of CH₂Cl₂ and 1 M HCl. The layers wereseparated, the organic portion was washed with H₂O, sat. aq. NaHCO₃, theemulsion formed filtered, the organic layer separated and dried (MgSO₄).After filtration through a pad of SiO₂ and subsequent washing withEtOAc, the solvant was evaporated and the residue purified bychromatography (SiO₂, pentane/EtOAc 1/1). The product was isolated as anoff white solid (311 mg, 0.79 mmol, 39%). Mp. 98-100° C. (M+1=394).

Functional Group Transformation According to Scheme 1N-(4-Butyloxy-phenyl)-2-(3-hydroxy-γ-pyranone)-carboxamide (59)

[0278]

[0279] A suspension ofN-(4-butyloxy-phenyl)-2-(3-benzyloxy-g-pyranone)-carboxamide (0.26 g,0.66 mmol) in 4 M HCl (25 mL) and EtOH (15 mL) was heated to 100° C. for3.5 h. The reaction mixture was cooled down and the suspension formedupon cooling was concentrated in vacuo. The residue was filtered off,washed with H₂O and MeOH, to give an off white solid (98 mg, 0.32 mmol,49%). Mp. 202-204° C.

EXAMPLE 13 Preparation of Pyrrolidin-3-carboxamides of Formula (I)Preparation of Starting Materials

[0280] The heterocyclic acid was prepared according to T. Högberg, P.Ström, M. Ebner, S. Rämsby J. Org. Chem. 1987, 52, 2033-2036:

Tert.butyl-(1-N-isopropyl-4-hydroxy-5-dioxo-2,5-dihydro-1H)-pyrrol-3-carboxylate

[0281]

[0282] To a solution of i-Propylamine (6.65 mL, 78 mmol) intert.-butanol (40 mL) under nitrogen was added dropwisetert.-Butylacrylate (11.3 mL, 78 mmol), the mixture was stirredovernight, then diethyloxalate was added (10.6 mL, 78 mmol) at r.t.Stirring was continued for 2 h, then tert.-BuOK was added (87 mg, 78mmol) and the mixture refluxed for 2 h, then cooled down and thevolatiles removed in vacuo. The crude product was dissolved in hotwater, acidified to pH 4. The resulting white precipitate was collectedby filtration, dried, to give 10.75 g of product (57%). Mp. 152° C.(M+1=186).

Coupling Procedure According to Scheme 1N-4-(phenoxy)phenyl-(1-N-isopropyl-4-hydroxy-5-dioxo-2,5-dihydro-1H)-pyrrol-3-carboxamide(72)

[0283]

[0284] To 0.24 g (1 mmol) oftert.-butyl-(1-isopropyl-4-hydroxy-5-dioxo-2,5-dihydro-1H)-pyrrol-3-carboxylatein dry toluene (5 mL) under N2 was added 4-Phenoxy-anilin (185 mg, 1mmol) and the mixture was refluxed for 4 h. After cooling to r.t.,crystals formed that were collected by filtration to give 70 mg of purematerial (0.2 mmol, 20%). Mp. 251° C. (M+1=353).

N-(4-(4-Trifluormethyl)phenoxy)phenyl-[(1-isopropyl-4-hydroxy-5-dioxo-2,5-dihydro-1H)-pyrrol]-3-carboxamide(73)

[0285]

[0286] ToEthyl-[(1-isopropyl-4-hydroxy-5-dioxo-2,5-dihydro-1H)-pyrrol]-3-carboxylate(0.2 g, 0.94 mmol), prepared as described by J. B. Campbell, J. W.Firor, J. Org. Chem. 1995, 60(23), 7687-7689, in toluene (5 mL) under N₂was added 4-(4-Trifluormethyl)phenoxy)-anilin (0.3 g, 1.2 mmol). Thereaction was refluxed for 2 h, then the solvant evaporated and theresidue purified by HPLC-chromatography. The product was obtained aswhite crystals (83 mg, 21%). (M−1=419)

Examples of Biological Activity of the Compounds of the InventionEXAMPLE 14 In Vivo Test on Alternaria brassicae (Leaf Spot of Crucifers)

[0287] An aqueous suspension, at a concentration of 1.5%, of the activematerial tested is obtained by grinding it finely in a formulation ofconcentrated suspension type. This aqueous suspension is then diluted inwater so as to obtain the desired active material concentration. Radishplants (Pernot variety) in starter cups, sown on a 50/50 peatsoil-pozzolana substrate and grown at 18-20° C., are treated at thecotyledon stage by spraying with the aqueous suspension described above.Plants, used as controls, are treated with an aqueous solution notcontaining the active material.

[0288] After 24 hours, the plants are contaminated by spraying them withan aqueous suspension of Alternaria brassicae spores (40,000 spores percm³). The spores are collected from a 12-13 day-old culture. Thecontaminated radish plants are incubated for 6-7 days at about 18° C.,under a humid atmosphere. Grading is carried out 6 to 7 days after thecontamination, in comparison with the control plants. Under theseconditions, good (at least 50%) or total protection is observed at adose of 500 g/ha with the following compounds: 1, 10, 11, 15, 17, 23,24, 25, 26, 28, 31, 32, 37, 42, 47, 48, 51, 52, 59, 60, 61, 62, 64, 65,66, 67, 68, 69, 70, 71, 72.

EXAMPLE 15 In Vivo Test on Septoria nodorum (Wheat Glume Blotch)

[0289] An aqueous suspension, at a concentration of 1.5%, of the activematerial tested is obtained by grinding it finely in a formulation ofconcentrated Suspension type. This aqueous suspension is then diluted inwater so as to obtain the desired active material concentration.

[0290] Wheat plants (Scipion variety) in starter cups, sown on a 50/50peat soil-pozzolana substrate and grown at 12° C., are treated at the1-leaf stage (10 cm tall) by spraying them with the aqueous suspensiondescribed above. Plants, used as controls, are treated with an aqueoussolution not containing the active material. After 24 hours, the plantsare contaminated by spraying with an aqueous suspension of Septorianodorum spores (500,000 spores per cm³). The spores are collected from aseven-day-old culture. The contaminated wheat plants are incubated for72 hours at about 18° C., under a humid atmosphere, and then for 14 daysat 90% relative humidity.

[0291] Grading is carried out 15 to 20 days after contamination, incomparison with the control plants. Under these conditions, good (atleast 50%) or total protection is observed, at a dose of 500 g/ha, withthe following compounds: 10, 16, 17, 19, 28, 32, 33, 39, 43, 46, 49, 52,53, 63, 64, 65, 66, 67, 68, 72.

EXAMPLE 16 In Vivo Test on Erisyphe graminis f. sp. tritici (PowderyMildew of Wheat)

[0292] An aqueous suspension, at a concentration of 1.5%, of the activematerial tested is obtained by grinding it finely in a formulation ofconcentrated suspension type. This aqueous suspension is then diluted inwater so as to obtain the desired active material concentration. Wheatplants (Audace variety) in starter cups, sown on 50/50 peatsoil-pozzulana substrate and grown at 12° C., are treated at the 1-leafstage (10 cm tall) by spraying with the aqueous suspension describedabove. Plants, used as controls, are treated with an aqueous solutionnot containing the active material. After 24 hours, the plants arecontaminated by dusting them with Erisyphe graminis f. sp. triticispores, the dusting being carried out using diseased plants.

[0293] Grading is carried out 7 to 14 days after the contamination, incomparison with the control plants. Under these conditions, good (atleast 50%) or total protection is observed, at a dose of 500 g/ha, withthe following compounds: 5, 11, 12, 13, 14, 15, 19, 22, 24, 25, 26, 27,28, 29, 30, 31, 32, 34, 35, 36, 37, 42, 44, 45, 49, 51, 55, 59, 64, 65,66, 67, 68, 69, 70, 71, 73.

Example 17 In Vivo Test on Septoria tritici (Leaf Spot of Wheat)

[0294] An aqueous suspension, at a concentration of 1.5%, of the activematerial tested is obtained by grinding it finely in a formulation ofconcentrated suspension type. This aqueous suspension is then diluted inwater so as to obtain the desired active material concentration. Wheatplants (Scipion variety) in starter cups, sown on a 50/50 peatsoil-pozzolana substrate and grown at 12° C., are treated at the 1-leafstage (10 cm tall) by spraying with the aqueous suspension describedabove. Plants, used as controls, are treated with an aqueous solutionnot containing the active material.

[0295] After 24 hours, the plants are contaminated by spraying them withan aqueous suspension of Septoria tritici spores (500,000 spores permL). The spores are collected from a 15-day-old culture and aresuspended in a nutrient solution composed of:

[0296] 1.5 g/L of gelatine

[0297] 0.5 g/L of sodium oleate

[0298] 24 g/L of PDB

[0299] The contaminated wheat plants are incubated for 72 hours at about20° C. and at 100% relative humidity, and then for 15 days at 80%relative humidity.

[0300] Grading is carried out 15 to 20 days after the contamination, incomparison with the control plants. Under these conditions, good (atleast 50%) protection is observed, at a dose of 500 g/ha, with thefollowing compounds: 1, 9, 15, 16, 18, 21, 22, 23, 24, 25, 26, 29, 30,31, 32, 33, 34, 35, 36, 37, 38, 39, 41, 42, 43, 45, 49, 50, 51, 52, 59,60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72.

EXAMPLE 18 In Vivo Test on Drechslera teres (Barley Net Blotch)

[0301] An aqueous suspension, at a concentration of 1.5%, of the activematerial. tested is obtained by grinding it finely in a formulation ofconcentrated suspension type. This aqueous suspension is then diluted inwater so as to obtain the desired active material concentration. Barleyplants (Express variety) in starter cups, sown on a 50/50 peatsoil-pozzolana substrate and grown at 12° C., are treated at the 1-leafstage (10 cm tall) by spraying with the aqueous suspension describedabove. Plants, used as controls, are treated with an aqueous solutionnot containing the active material.

[0302] After 24 hours, the plants are contaminated by spraying them withan aqueous suspension of Dreschslera teres spores (12,000 spores permL). The spores are collected from a 12-day-old culture. Thecontaminated wheat plants are incubated for 24 hours at about 20° C. andat 100% relative humidity, and then for 12 days at 80% relativehumidity.

[0303] Grading is carried out 12 days after the contamination, incomparison with the control plants. Under these conditions, good (atleast 50%) protection is observed, at a dose of 500 g/ha, with thecompounds described as example: 9, 13, 14, 15, 18, 20, 21, 22, 24, 26,27, 30, 31, 32, 33, 34, 35, 36, 37, 41, 43, 45, 47, 49, 62, 69, 70, 72.

EXAMPLE 19 In Vivo test on Rhynchosporium secalis (Barley Leaf Scald)

[0304] An aqueous suspension, at a concentration of 1.5%, of the activematerial tested is obtained by grinding it finely in a formulation ofconcentrated suspension type. This aqueous suspension is then diluted inwater so as to obtain the desired active material concentration. Barleyplants (Express or Barrack variety) in starter cups, sown on a 50/50peat soil-pozzolana substrate and grown at 12° C., are treated at the1-leaf stage (10 cm tall) by spraying with the aqueous suspensiondescribed above. Plants, used as controls, are treated with an aqueoussolution not containing the active material.

[0305] After 24 hours, the plants are contaminated by spraying them withan aqueous suspension of Rhynchosporium secalis spores (800,000 sporesper mL). The contaminated wheat plants are incubated for 48 hours atabout 20° C. and at 100% relative humidity, and then for 12/14 days at80% relative humidity.

[0306] Grading is carried out 12/14 days after the contamination, incomparison with the control plants. Under these conditions, good (atleast 50%) protection is observed, at a dose of 500 g/ha, with thefollowing compound described as example: 32.

EXAMPLE 20 In Vivo Test on Puccinia recondita (Wheat Brown Rust)

[0307] An aqueous suspension, at a concentration of 1.5%, of the activematerial tested is obtained by grinding it finely in a formulation ofconcentrated suspension type, This aqueous suspension is then diluted inwater so as to obtain the desired active material concentration. Wheatplants (Scipion variety) in starter cups, sown on a 50/50 peatsoil-pozzolana substrate and grown at 12° C., are treated at the 1-leafstage (10 cm tall) by spraying with the aqueous suspension describedabove. Plants, used as controls, are treated with an aqueous solutionnot containing the active material.

[0308] After 24 hours, the plants are contaminated by spraying them withan aqueous suspension of Puccinia recondita spores (150,000 spores permL). The contaminated wheat plants are incubated for 24 hours at about20° C. and at 100% relative humidity, and then for 10 days at 70%relative humidity.

[0309] Grading is carried out 10 days after the contamination, incomparison with the control plants. Under these conditions, good (atleast 50%) protection is observed, at a dose of 500 g/ha, with thefollowing compounds described as example: 6, 10, 11, 12, 13, 14, 15, 28,29, 30, 31, 34, 37, 42, 45, 46, 50, 51, 52, 62, 72.

EXAMPLE 21 In Vivo Test on Botrytis cinerea (Cucumber Grey Mould)

[0310] An aqueous suspension, at a concentration of 1.5%, of the activematerial tested is obtained by grinding it finely in a formulation ofconcentrated suspension type. This aqueous suspension is then diluted inwater so as to obtain the desired active material concentration.Cucumber plants (Marketer variety) in starter cups, sown on a 50/50 peatsoil-pozzolana substrate and grown at 18-20° C., are treated at thecotyledon Z11 stage by spraying with the aqueous suspension describedabove. Plants, used as controls, are treated with an aqueous solutionnot containing the active material.

[0311] After 24 hours, the plants are contaminated by depositing dropsof an aqueous suspension of Botrytis cinerea spores (150,000 spores perml) on upper surface of the leaves. The spores are collected from a15-day-old culture and are suspended in a nutrient solution composed of:

[0312] 20 g/L of gelatine

[0313] 50 g/L of cane sugar

[0314] 2 g/L of NH4NO3

[0315] 1 g/L of KH2PO4

[0316] The contaminated cucumber plants are settled for 5/7 days in aclimatic room at 15-11° c. (day/night) and at 80% relative humidity.

[0317] Grading is carried out 5/7 days after the contamination, incomparison with the control plants. Under these conditions, good (atleast 50%) protection is observed, at a dose of 500 g/ha, with thefollowing compounds described as example 5, 24, 30, 37, 45, 67, 69, 70.

1. Compound of general formula (I):

in which: Het represents a five or six membered saturated or partiallyunsaturated or aromatic ring containing one or two heteroatoms of thegroup N, O, and S which can be identical or different, in which theheterocycle is substituted by —(C═O)-Q¹-T-Q², -Gz and Y in an adjacentmanner, such that the substituent -Gz is adjacent to both Y and—(C═O)-Q¹-T-Q² and that —(C═O)-Q¹-T-Q², -Gz and Y are not linked withheteroatoms of Het; n represents 0, 1, 2 or 3; X is chosen in the groupconsisting of hydrogen, halogen, —R¹ and —SR¹; Y is chosen in the groupconsisting of

—(C═O)—R³, —NH₂, —NHR¹, —NH—(C═O)—R² , —(SO₂)—R¹ and O; G is chosen inthe group consisting of —(CH₂)_(k)—, —O—, —O—(C═O)— and —O—(C═O)—O—; zis chosen in the group consisting of hydrogen, —R¹ and halogen; Q¹ ischosen in the group consisting of

T is chosen in the group consisting of —O—, —(CH₂)_(q)— and —S—; Q² ischosen in the group consisting of hydrogen, —R¹, —R⁴,methylbenzothiazolyl,

j, k, m, p, r and t are independently chosen as being 0, 1, 2 or 3; hrepresents an integer between 0 and 10; R¹ is C₁-C₄ alkyl or C₁-C₄alkoxyalkyl; R² is oxy-(C₁-C₄)alkylene or oxy-(C₁-C₄)alkyl; R³ is —OH,—OR¹ or —NH₂; and R⁴ is halogen, alkyl or halogenoalkyl; as well asN-oxides, geometrical and/or optical isomers, enantiomers and/ordiastereoisomers, tautomeric forms, salts and metal and metalloidcomplexes thereof; with proviso that —(C═O)-Q¹-T-Q² is not in the2-position when Het represents a pyridine
 2. Compound according to claim1, characterised in that Het is a five membered heterocycle.
 3. Compoundaccording to claim 2, characterised in that Het is chosen in the groupconsisting of thiophene, pyrrole, isoxazole, isothiazole, pyrazole andpyrrolidine.
 4. Compound according to claim 3, characterised in that:Het is thiophene, represents 0 or 1; X is —H; Y is chosen in the groupconsisting of —NH₂, —CO₂H, —NHC(O)R² and —S(O)₂—R¹; R¹ is C₁-C₄ alkyl;R² is oxy-(C₁-C₄)alkylene; G is —O—; Z is —H or —R¹; Q¹ is

T is —O— or —(CH₂)_(q)—; Q² is chosen in the group consisting of:

p and t are independently chosen as being 0, 1 or 2; q is
 0. 5. Compoundaccording claim 3, characterised in that: Het is pyrrole; n represent 0,1 or 2; X is —H or —R¹; Y is chosen in the group consisting of —NH₂,—C(O)R³, —NHC(O)R² and —S(O)₂—R¹; R¹ is C₁-C₄ alkyl; R² isoxy-(C₁-C₄)alkylene; R³ is —OH, oxy-(C₁-C₄)alkyl oroxy-(C₁-C₄)alkoxyalkyl; G is —O—; Z is —H or —R¹; p and t areindependently chosen as being 0, 1 or 2; Q¹ is

T is —O— or —(CH₂)_(q)—; q is 0; Q² is chosen in the group consisting ofhydrogen, —R¹, —R⁴,


6. Compound according to claim 3, characterised in that: Het isisoxazole; n is 0; Y is chosen in the group consisting of —NH₂, —C(O)R³,—NHC(O)R² and —S(O)₂—R¹; R¹ is C₁-C₄ alkyl; R² is oxy-(C₁-C₄)alkylene oroxy-(C₁-C₄)alkyl; R³ is —OH, oxy-(C₁-C₄)alkyl or oxy-(C₁-C₄)alkoxyalkyl;G is —O—; Z is —H; p and t are independently chosen as being 0, 1 or 2;Q¹ is

T is —O— or —(CH₂)_(q)—; q is 0; Q² is chosen in the group consisting of


7. Compound according to claim 3, characterised in that: Het ispyrrolidin; n is 1 or 2; Y is O; G is —O—; Z is —H; p and t areindependently chosen as being 0, 1 or 2; Q¹ is

T is —O— or —(CH₂)_(q)—; q is 0; Q² is chosen in the group consisting ofhydrogen, —R¹, —R⁴,


8. Compound according to claim 1, characterised in that Het is a sixmembered heterocycle.
 9. Compound according to claim 8, characterised inthat Het is chosen in the group consisting of pyridine, such that—(C═O)-Q¹-T-Q² is attached in 3-position, 1,2-pyridazine, such that—(C═O)-Q¹-T-Q² is attached in 3-position and pyranone, such that—(C═O)-Q¹-T-Q² is attached in 2-position.
 10. Compound according toclaim 9, characterised in that: Het is pyridine, such that—(C═O)-Q¹-T-Q² is attached in 3-position; n represent 0, 1 or 2; X is —Hor —R¹; Y is chosen in the group consisting of

—(C═O)—R³, —NH₂, —NHR¹, —NH—(C═O)—R², —(SO₂)—R¹ and —O; R¹ is C₁-C₄alkyl; R² is oxy-(C₁-C₄)alkylene or oxy-(C₁-C₄)alkyl; R³ is —OH,oxy-(C₁-C₄)alkyl or oxy-(C₁-C₄)alkoxyalkyl; G is —O—; Z is —H or —R¹; pand t are independently chosen as being 0, 1 or 2; Q¹ is

T is —O— or —(CH₂)_(q)—; q 0,; Q² is chosen in the group consisting of:


11. Compound according to claim 9, characterised in that: Het ispyranone, such that —(C═O)-Q¹-T-Q² is attached in 2-position; n is 0, 1or 2; x is —H or —R¹ Y is O; R¹ is C₁-C₄ alkyl; G is —O—; Z is —H; p, qand t are independently chosen as being 0, 1 or 2; Q¹ is

T is —O— or —(CH₂)_(q)—; Q² is chosen in the group consisting of


12. Process for preparing the compound according to any of the claims 1to 11, characterised by the reaction Scheme 1

by effecting a reaction between a substituted heterocyclic acid or acidderivative of general formula (a) with a nucleophilic compound ofgeneral formula (b), wherein Y′ chosen in the group consisting of

halogen, —NH₂, —NO₂, —(C═O)—R³, —NHR¹, —NH—(C═O)—R², —(SO₂)—R¹ and O; G′is chosen in the group consisting of —(CH₂)_(k)—, —O—, —O—(C═O)— and—O—(C═O)—O—; z is chosen in the group consisting of hydrogen, —R¹,halogen and benzyl; X, Y, G, z, Q¹, T, Q² are as defined in claim 1; Wrepresents a hydroxy group (—OH) present in the free acid —(C═O)—OH or agroup obtained after activation of the free acid —P—OH.
 13. Fungicidalcomposition comprising an effective amount of a compound according toany of the claims 1 to 11 and an agriculturally acceptable support. 14.Fungicidal composition according to claim 13 further comprising asurfactant.
 15. Fungicidal composition according to either of claims 13and 14, comprising from 0.05% to 99% by weight of active material. 16.Method for preventively or curatively combating the phytopathogenicfungi of crops, characterised in that an effective and non-phytotoxicamount of a composition according to claim 13 to 15 is applied to theplant seeds or to the plant leaves and/or to the fruits of the plants orto the soil in which the plants are growing or in which it is desired togrow them.
 17. Method according to claim 16, in which the dose of activematerial applied is between 10 g and 800 g of active material perhectare, in the case of foliar treatments.
 18. Method according to claim17, in which the dose of active material applied is between 50 g and 300g of active material per hectare in the case of foliar treatments. 19.Method according to claim 16, in which the dose of active materialapplied is between 2 and 200 g of active material per 100 kg of seed, inthe case of seed treatments.
 20. Method according to claim 19, in whichthe dose of active material applied is between 3 g and 150 g per 100 kgof seed, in the case of seed treatments.